tbuckley/cabot-search huggingface dataset:
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in subgroups defined by response to 1L chemotherapy.
Authors: Begoña Pérez-Valderrama, Thomas Powles, Srikala S. Sridhar, Claudia Caserta, Yohann Loriot, Shilpa Gupta, Joaquim Bellmunt, Cora N. Sternberg, Jing Wang, Nuno Costa, Robert J Laliberte, Alessandra Di Pietro, Se Hoon Park, Petros Grivas
Journal: Journal of Clinical Oncology (2022)

4559 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based chemotherapy. We report exploratory analyses in subgroups defined by response to 1L chemotherapy (complete response [CR], partial response [PR], or stable disease [SD]) after ≥2 years of follow-up. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC (n = 350) or BSC alone (n = 350), stratified by best response to 1L chemotherapy (CR/PR vs SD) and visceral vs nonvisceral disease at start of 1L chemotherapy. Results: At data cutoff (June 4, 2021), median follow-up in both arms was ≥38 months. OS and PFS were longer in the avelumab + BSC vs BSC alone arm in all subgroups (Table). Median duration of study treatment and incidence of grade ≥3 treatment-emergent adverse events (TEAEs) in subgroups are shown in the Table. In the avelumab + BSC vs BSC alone arm, respectively, subsequent second-line anticancer drug therapy was received by: CR subgroup, 50.0% vs 74.2%; PR subgroup, 58.3% vs 71.8%; and SD subgroup, 46.4% vs 70.4%. Conclusions: Long-term follow-up from JAVELIN Bladder 100 continues to show prolonged OS and PFS with avelumab + BSC vs BSC alone irrespective of response (CR, PR, or SD) to 1L chemotherapy and despite a higher proportion of pts in the BSC alone arm receiving subsequent therapy. Long-term safety was consistent across subgroups. These findings further support avelumab 1L maintenance as standard of care for all pts with aUC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Surgical treatment of locally advanced retroperitoneal sarcomas.
Authors: Yuriy A. Gevorkyan, Oksana V. Katelnitskaya, Oleg I. Kit, Andrey A. Maslov, Natalya V. Soldatkina, Dmitriy S. Petrov, Vladimir E. Kolesnikov, Dmitriy A. Savchenko, Roman E. Tolmakh, Andrey V. Dashkov, Sergei A. Ilchenko, Larisa N. Vashchenko, Vladimir N. Kasyanenko
Journal: Journal of Clinical Oncology (2022)

e23552 Background: Surgery with negative resection margins is now considered the main treatment for retroperitoneal sarcomas improving the survival and quality of life of patients. The most common obstacle to surgery with R0 resection in locally advanced tumors is the involvement of the great vessels. The purpose of this study was to analyze the results of surgical treatment in patients with locally advanced retroperitoneal sarcomas involving the inferior vena cava or iliac veins. Methods: The study included 34 cancer patients who underwent tumor resection with major vessel resection in 2015-2021. The mean tumor size was 15.5 cm (from 6 to 41 cm). The most common tumors were moderately differentiated liposarcoma (38%) and pleomorphic liposarcoma (26%). Results: Resection of the inferior vena cava was performed in 19 cases, resection of the iliac segment - 15. Circular vein resection without reconstruction was performed in 5 patients, wedge resection - 7, segmental resection with end-to-end anastomosis - 1, replacement of the venous segment with a prosthesis - 25. Resection of adjacent organs was required in 26.5% of surgical interventions. According to the final pathoanatomical examination, the rate of complete tumor resections (R0-1) was 88.2%. During the 30-day postoperative period, mortality and complication rates were acceptable, 29% and 0%, respectively. During the follow-up period, the median disease-free survival was 13 months, and the median overall survival was not reached. Conclusions: Surgical interventions expanded due to resection of the major veins in locally advanced retroperitoneal sarcomas allow achieving a high rate of radical tumor resection and improving relapse-free and overall survival rates.
A phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody, in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Jermaine Coward, Ben Markman, Adnan Nagrial, Afaf Abed, Imogen Walpole
Journal: Journal of Clinical Oncology (2022)

2603 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia using an accelerated "3+3" design. Patients (pts) with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles. Treatment continuation beyond cycle 4 is possible if subject is deriving an ongoing clinic benefit. The safety, tolerability and preliminary efficacy data will be analyzed. Results: Between 29 Jul 2020 and 30 Dec 2021, a total of 20 patients with various advanced solid tumors were enrolled including 0.03 mg/kg (n = 3), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1.0 mg/kg (n = 8) and 3.0 mg/kg (n = 3). The median age was 60 years (range 33-75). Baseline ECOG scores were 0 (13 pts) and 1 (7 pts). 8 pts had received prior immunotherapy (anti-PD-1/PD-L1 or anti-PD-1+CTLA-4mAb). Dose escalation has been completed and only one dose-limiting toxicity relating to YH003 was observed at 1.0 mg/kg (grade 3 transaminitis). The maximum tolerated dose (MTD) was not reached. 13 (65%) pts experienced any grade treatment related adverse events (TRAEs). The most common (≥ 10%) TRAEs were infusion reaction, pyrexia, fatigue, nausea, diarrhea, transaminitis. Most TRAEs were grade 1 or 2. Only 3 (15.0%) pts experienced Grade 3 TRAEs including one each of neutropenia (YH003 0.3 mg/kg), transaminitis (YH003 1.0 mg/kg) and elevated lipase (Toripalimab 0.1 mg/kg). Only 2 pts have permanently discontinued treatment due to TRAEs including grade 3 transaminases increased and grade 2 hepatitis. There were no ≥grade 4 TRAEs and drug related serious adverse events (SAEs) were not observed. Among 14 pts assessable for response, the overall response rate (ORR) was 14.3% (2/14) and disease control rate (DCR) was 35.7% (5/14). One partial response (PR) occurred in a pt with anti-PD1/anti-CTLA4 refractory ocular melanoma with liver metastases (YH003 0.1 mg/kg) who continued on treatment for &gt; 1 year. The other PR occurred in a pt with Non-Small Cell Lung Carcinoma (YH003 1.0 mg/kg) who continued on treatment for almost 9 months. Conclusions: YH003 was well tolerated up to 3.0 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.
Comparison of survival outcomes of patients with newly diagnosed glioblastoma treated with standard chemoradiation in and outside of clinical trials.
Authors: Rifaquat Rahman, Gilbert Youssef, Steffen Ventz, Robert Redd, Jon McDunn, William Louv, Brian Michael Alexander, Patrick Y. Wen, Lorenzo Trippa
Journal: Journal of Clinical Oncology (2022)

2051 Background: Randomized clinical trials use stringent eligibility criteria to select patients which can raise concerns about generalizability of study results. Recent interest in external controls and new trial designs has increasingly focused on the possible use of real-world data sources. We examined potential differences of survival outcomes in clinical trial and real-world datasets in newly diagnosed glioblastoma. Methods: Patient-level data from 4 independent datasets were analyzed. Non-trial data were derived from an institutional dataset of 453 patients with newly diagnosed glioblastoma treated outside of a clinical trial with standard radiation therapy with concurrent and adjuvant temozolomide at a large academic center. Trial patients included patients on the control arm of several multi-institutional trials (NCT00689221, n = 273; NCT00813943, n = 89; NCT00943826; n = 459) and patients treated on trial at our institution (n = 210). Non-trial patients were compared with each of the 4 clinical trial datasets in pairwise comparisons with Cox regression with adjustments for age, sex, extent of resection, KPS and MGMT status. Results: Patient-level data from 1,484 patients were analyzed. Non-trial patients were older compared to patients in the multi-institutional trials (mean 58.6 vs. 56.1 years (NCT00943826), 53.9 years (NCT00813943), 55.7 years (NCT00689221); p &lt; = 0.001). The non-trial cohort had fewer women (43.5% vs. 35.9%, p = 0.02), greater proportion of lower KPS patients (47% KPS &lt;90 vs. 31% KPS &lt;90, p &lt; 0.001) and greater proportion of MGMT methylated patients (49% vs. 33%, p &lt; 0.001) compared to NCT00943826 patients. There were no other significant differences between patient characteristics of non-trial patients and the 4 trial datasets. Trial participation was not associated with improved survival in multivariable analysis after adjustments for clinical covariates (non-trial patients vs. each trial dataset; Table, P &gt; 0.05). Conclusions: Glioblastoma patients treated on multi-institutional clinical trials that were included in our analysis did not have statistically significant differences in survival compared to patients treated outside of a clinical trial at a large academic center after adjustment for relevant variables. Our findings support the possible use of real-world data in the development of external control arms for future trials in newly diagnosed glioblastoma. [Table: see text]
A single-center experience of 98 patients (pts) with regionally metastatic Merkel cell carcinoma (MCC) of known (MCCKP) and unknown (MCCUP) primary at presentation.
Authors: Brandon Cope, Russell G. Witt, Yi-Ju Chiang, Riyad Navroz Seervai, Sarah B. Fisher, Anthony Lucci, Jennifer Ann Wargo, Jeffrey Edwin Lee, Ahsan Saleem Farooqi, Andrew Bishop, Jeffrey E. Gershenwald, Ryan Goepfert, Michael K.K. Wong, Beverly Ashleigh Guadagnolo, Merrick I. Ross, Phyu P Aung, Deverati Mitra, Emily Zhi-Yun Keung
Journal: Journal of Clinical Oncology (2022)

9576 Background: MCC is a rare skin cancer historically associated with poor survival rates and which is increasing in incidence. A small number of retrospective series suggest that MCCUP may be associated with better prognosis than MCCKP while others report worse outcomes. Recent advances in immunotherapy have changed the multimodal treatment landscape and outcomes of advanced MCC pts. We describe our experience with the management and outcomes of pts presenting with regional MCC metastasis of known and unknown primary origin. Methods: A retrospective review of pts with clinical regional disease at MCC diagnosis treated at our institution from 3/2003-3/2021 was performed. Clinicopathologic variables and outcomes were assessed. Overall survival (OS), recurrence-free survival (RFS) and progression-free survival (PFS) were estimated by the Kaplan Meier method. Results: Of 98 pts with regional disease on exam at presentation, 56 (57%) had MCCUP and 42 (43%) had MCCKP. Median follow-up from diagnosis to last follow-up or death was 33 months. Pts were generally older (MCCUP vs MCCKP: 68.7 vs 73.1 years), male (MCCUP vs MCCKP: 82% vs 74%) and Caucasian (MCCUP vs MCCKP: 84% vs 83%). Over half the pts had a history of another malignancy (MCCUP vs MCCKP: 52% vs 60%) with 9% and 14% being immunocompromised at diagnosis, respectively. After completion of staging workup, MCCUP pts had earlier stage disease at presentation compared with MCCKP pts (stage IIIA: 80% vs 55%, IIIB: 5% vs 31%, IV: 15% vs 14%, respectively). The cervical nodal basin was most commonly involved in MCCUP pts while regional disease was more varied in MCCKP pts (MCCUP vs MCCKP: cervical 54% vs 28%, axillary 15% vs 33%, inguinal 33% vs 3%, inguinal and pelvic 0% vs 11%, in transit 0% vs 14%). Formal lymphadenectomy (LND) was performed in 27 (48%) and 18 (43%) of MCCUP and MCCKP pts, respectively. Of these pts, 33% and 50% received neoadjuvant systemic therapy, most commonly immunotherapy; 70% and 55% received adjuvant radiotherapy. MCCUP pts had better outcomes compared to MCCKP pts (Table), with longer RFS in pts who underwent LND (not reached [NR] vs 13.1 months) as well as longer PFS in pts who did not undergo LND (17 vs 9 months) with longer OS in both subgroups (LND: NR vs 102.7 months; no LND: 74.4 vs 48.7 months). Conclusions: MCCUP patients with regional disease on exam at presentation have improved survival compared to MCCKP. Current stage III survival estimates may underestimate survival in patients with resectable disease. [Table: see text]
Atezolizumab and bevacizumab in patients with relapsed mesothelioma: MIST4—a phase IIa trial with cellular and molecular correlates of efficacy.
Authors: Dean Anthony Fennell, Amy King, Amy Branson, Shaun Barber, Alastair Greystoke, Sean Dulloo, Charlotte Poile, James Harber, Molly Scotland, Liz Darlison, Amrita Bajaj, Bruno Morgan, Cassandra Brookes, Peter Wells-Jordan, Catherine Jane Richards, Anne Thomas
Journal: Journal of Clinical Oncology (2022)

8560 Background: Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM) however the factors that determine sensitivity are unknown. Combined inhibition of vascular endothelial growth factor (VEGF) may potentiate efficacy through remodelling of the tumour microenvironment and inhibition of angiogenesis. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis and to uncover cellular and molecular determinants of efficacy as arm 4 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST4). Methods: Patients with any histological subtype or site of MM (pleural or peritoneal) were enrolled. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1 st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Atezolizumab 1200mg iv q3w with bevacizumab 15mg/kg iv q3w (AtzBev). Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Baseline BAP1, p16ink4a, PD-L1 (DAKO22C3), gut microbiome 16s RNA metagenomics, multiplex immunofluorescence, and whole exome and RNA transcriptome sequencing was conducted to explore cellular and molecular correlates of sensitivity. Results: Between January 2020 and February 2021, 26 patients with MM started treatment and received at least one dose of AtzBev. The median age of pts was 68 (range, 44-80) years, 69% were male, 77% epithelioid, 85% ECOG PS1, &gt; 1 prior systemic therapy 54%. The median cycles of Atz dosing was 4.5 (IQR, 2-8) and Bev dosing was 4.5 (IQR, 2-7). DCR12w: 53.8% (95% confidence limit (CI), 33.4% – 73.4%), DCR24w: 23.1% (95%CI, 9.0% – 43.6%). Best responses (evaluable within 24w): partial – 3.8% (95%CI, 0.1- 19.6%); stable disease – 69.2% (48.2 – 85.7%); progression – 15.4% (4.4 – 34.9%). Adverse events (any cause): ≥ grade 3 toxicities affected 35% of pts. Conclusions: MiST4 met its primary endpoint however responses were heterogeneous. Analysis of cellular and molecular correlates are ongoing and will be presented. Clinical trial information: NCT03654833.
A phase II study of KN046 monotherapy as 2<sup>nd</sup> line and above treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Jin Gang, Shiwei Guo, Yanqiao Zhang, Yue Ma, Xiaodong Guo, Xiaocui Zhou, Qin Yu
Journal: Journal of Clinical Oncology (2022)

e16305 Background: Pancreatic cancer is a malignancy with poor prognosis and high mortality ranking 7 th worldwide and with a 5-year survival rate of 10.8%. More than 50% pts are diagnosed at the late stage. The monoclonal antibodies of immune checkpoint inhibitors are also being investigated but has very limit progression free survival (PFS) and overall survival (OS) benefit. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) in a phase 2 study arm 2 (NCT04324307) was reported before. Here, we report the efficacy and safety of KN046 as a monotherapy in the 2 nd line and above setting (arm1). Methods: This ongoing phase 2 trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and failed to at least one systemic anti-tumor treatment in arm 1. Single agent of KN046 (5mpk, Q2W) were administered until disease progression or intolerable toxicity. Tumor response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed objective response rate (ORR). Secondary endpoints including disease control rate (DCR), PFS, OS and safety, etc. Results: As of Jan 10, 2022, 21pts were enrolled, median (range) age was 57 (51-64) years, 14 (66.7%) pts ECOG 1, 16 (76.2%) pts had distant metastases, and 11 (52,4%) pts had received ≥2 lines systemic treatment. Median KN046 exposure time was 4.1(2.1,6,4) wks. 9 pts were included in the efficacy analysis with 1 PR and 3 SD. 21 pts in the safety analysis. Confirmed ORR was 11.1% (95% CI: 0.28,48.25), and DCR was 44.4% (95% CI: 13.7,78.8). Median PFS was 2.1 months (95% CI:1.61̃7.29), PFS rate in 6 and 9 months were 31.4% and 21%, respectively. Median OS was 7.5months (95% CI:3.02-NR), OS rate in 6 and 9 months were 61.3% and 49.5%, respectively. The incidence of KN046 related treatment-emergent adverse events (TRAE) was 71.4% (15/21), with 14.3% (3/21) ≥grade 3 TRAEs. Two pts experienced TRAE leading to discontinuation. The most common TRAEs (≥10%) were rash (n=6, 28.6%), alanine aminotransferase increased, chills, γ-glutamyl transferase increased and platelet count decreased (n = 3, 14.3%, respectively). No TRAE leading to death occurred. Conclusions: KN046, a bispecific antibody as 2 nd line and above monotherapy for unresectable locally advanced or metastatic PDAC patients demonstrated a good PFS and OS benefit as well as acceptable safety profile, supporting KN046 in combination of chemotherapy as first line treatment. Clinical trial information: NCT04324307.
Using CT-based body composition metrics and frailty index in predicting survival among older adults with cancer.
Authors: Smith Giri, Elizabeth Feliciano, Christian Harmon, Kelly Kenzik, Mustafa Al-Obaidi, Ijeamaka Anyene, Mirza Faisal Beg, Vincent Tze Yang Chow, Karteek Popuri, Leon Lenchik, Bette Jane Caan, Grant Richard Williams
Journal: Journal of Clinical Oncology (2022)

12057 Background: Older adults with cancer are at an increased risk of treatment related toxicities and excess mortality during cancer treatment. While altered body composition and frailty are associated with worse survival among older adults with cancer, no prior study has examined their combined influence on survival prediction. Methods: Prospective study of older adults (≥60 years) undergoing geriatric assessment (GA) at initial visit with a medical oncologist at UAB from 9/2017-07/2021 with available abdominal computed tomography (CT) within 60 days of GA. Using multi-slice CT images from T12 to L5 level, volumetric skeletal muscle (SMV), visceral (VATV) and subcutaneous (SATV) adipose tissues, and skeletal muscle density (SMD), were derived. Sex-specific z-scores for each measure were determined. A 44-item frailty index was obtained, using the deficit accumulation model. Overall survival (OS) was defined as time from GA to death or last follow-up (11/8/2021). Kaplan-Meier estimates of survival rates were compared using log-rank statistics. Multivariable cox regression models were used to predict OS in a random sub-sample (1:1 split of training:validation set), sequentially adding frailty and each body composition measure and assessing improvement with likelihood ratio tests and Harrel’s C statistic. Results: 815 patients were included (median age 68 years, 61% men, and 75% non-Hispanic Whites. 73% had gastrointestinal malignancies (stage III, 25%, stage, IV 48%). 32% were frail, 31% pre-frail. There was a weak negative correlation between height-adjusted SMV and frailty (r = -0.16), particularly among men (r -0.24). Over a median follow-up of 25.7 months (range 0.3-49.6 months), 268 patients (33%) died. The 2-year survival rate was 75.9%, 68.5% and 52.2% among robust, pre-frail and frail (log-rank p &lt;.001), respectively. In multivariable models adjusted for age, sex, race, cancer type and cancer stage, being frail (vs robust) (Hazards Ratio, HR = 2.32; 95%CI: 1.69-3.2; p &lt;.001) and higher skeletal muscle volume (HR = 0.85; 95%CI: 0.72-0.99; p= 0.04, per SD increment) were independently associated with OS. Adding body composition and frailty to clinical variables led to significant improvement in prediction (Harrel’s C increased from 0.69 to 0.74). In the validation set, discrimination was similar (Harrel’s C = 0.72) and plots suggested good model calibration. Conclusions: CT-based body composition metrics and frailty are independent predictors of OS among older adults with cancer and improve survival prediction compared to routine clinical risk factors.